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Valsartan in Acute Myocardial Infarction Trial Investigators - VALIANT
Description:
The goal of the trial was to evaluate the effect of the angiotensin-receptor blocker (ARB) valsartan, the angiotensin-converting enzyme (ACE) inhibitor captopril, and the combination of the two on mortality in patients with myocardial infarction (MI) complicated by left ventricular (LV) systolic dysfunction, heart failure, or both.
Hypothesis:
Treatment with valsartan, an ARB, alone or in combination with captopril, an ACE inhibitor, would result in better survival than treatment with a proven ACE inhibitor regimen.
Study Design
Study Design:
Patients Enrolled: 14,703
Mean Follow Up: Median 24.7 months
Mean Patient Age: Mean age 65 years
Female: 31
Mean Ejection Fraction: Mean baseline LVEF 35%
Patient Populations:
Age ≥18 years of age; acute MI within 10 days prior complicated by clinical or radiologic signs of heart failure, evidence of LV systolic dysfunction (an ejection fraction [EF] ≤35% on echocardiography or contrast angiography and ≤40% on radionuclide ventriculography), or both; systolic blood pressure >100 mm Hg; and serum creatinine concentration <2.5 mg per deciliter
Exclusions:
Previous intolerance or contraindication to an ACE inhibitor or ARB, clinically significant valvular disease, another disease known to limit life expectancy severely, and the absence of written informed consent
Primary Endpoints:
Death from any cause during follow-up
Secondary Endpoints:
Death from cardiovascular causes, reinfarction, or hospitalization for heart failure
Drug/Procedures Used:
Patients were randomized to valsartan monotherapy (20 mg; n=4,909), valsartan (20 mg) plus captopril (6.25 mg; n=4,885), or captopril monotherapy (6.25 mg; n=4,909). Doses were increased in four steps, with the final step (160 mg of valsartan twice daily, 80 mg of valsartan twice daily and 50 mg of captopril three times daily, or 50 mg of captopril three times daily) to be reached by the three-month follow-up visit.
Principal Findings:
In the valsartan group, 979 patients (19.9%) died compared with 941 patients (19.3%) in the valsartan/captopril group and 958 patients (19.5%) in the captopril group (hazard ratio [HR] in the valsartan group as compared with the captopril group, 1.00, 97.5% confidence interval [CI] 0.90-1.11, p=0.98; HR in the valsartan/captopril group vs. captopril group, 0.98, 97.5% CI 0.89-1.09, p=0.73). The upper limit of the one-sided 97.5% CI for the comparison of the valsartan group with the captopril group met the prespecified margin for noninferiority with regard to mortality (p=0.004). Death from cardiovascular causes, reinfarction, or hospitalization for heart failure did not differ in the valsartan group (31.1%) compared with the captopril group (31.1%, HR 0.95, 95% CI 0.88-1.03, p=0.20) or compared with the valsartan/captopril group (31.9%, HR 0.97, 95% CI 0.89-1.05, p=0.37).
The comparison of the valsartan group with the captopril group did meet the criteria for noninferiority for the composite endpoint of fatal and nonfatal cardiovascular events (p<0.001). Adverse events resulting in dose changes occurred most frequently in the valsartan/captopril arm (34.8%) versus the valsartan group (29.4%) or the captopril arm (28.4%). In the valsartan group, hypotension and renal dysfunction occurred more frequently, while in the captopril group, cough, rash, and taste disturbance occurred more frequently.
Interpretation:
Among patients with MI complicated by LV systolic dysfunction, heart failure, or both, treatment with valsartan, an ARB, alone or in combination with captopril, an ACE inhibitor, did not meet the primary endpoint of all-cause mortality compared with captopril monotherapy for superiority, but did meet the criteria for noninferiority.
The lack of improvement with combination therapy in the present trial is in contrast to the recent CHARM-Added trial, which showed a reduction in cardiovascular death or heart failure hospitalizations associated with combination therapy with the ARB candesartan and an ACE inhibitor in patients with heart failure. However, even in the CHARM-Added trial, there was an increase in study drug discontinuation due to adverse events of hypotension and increased creatinine.
References:
Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both. N Engl J Med 2003;349:1893-906.
Presented by Dr. Marc A. Pfeffer at the November 2003 American Heart Association Annual Scientific Sessions, Orlando, FL.
Keywords: Myocardial Infarction, Follow-Up Studies, Hypotension, Blood Pressure, Creatinine, Valine, Tetrazoles, Captopril, Radionuclide Ventriculography, Benzimidazoles, Angiotensin II Type 1 Receptor Blockers, Heart Failure, Confidence Intervals, Cough, Ventricular Dysfunction, Left, Exanthema, Echocardiography
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